NM_000651.6:c.3994C>T

Variant names:

• chr1-207567865-C-T
• rs201131753
• NM_000651.6:c.3994C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000651.6(CR1):​c.3994C>T​(p.His1332Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000166 in 1,610,828 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00086 (13 hom., cov: 30)
  • Exomes 𝑓: 0.000094 (16 hom.)
• Consequence: CR1 NM_000651.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.480

Genes affected

CR1 (HGNC:2334): (complement C3b/C4b receptor 1 (Knops blood group)) This gene is a member of the receptors of complement activation (RCA) family and is located in the 'cluster RCA' region of chromosome 1. The genome is polymorphic at this locus with allele-specific splice variants encoding different isoforms, based on the presence/absence of long homologous repeats (LHRs). The gene encodes a monomeric single-pass type I membrane glycoprotein found on erythrocytes, leukocytes, glomerular podocytes, and splenic follicular dendritic cells. The Knops blood group system is a system of antigens located on this protein. The protein mediates cellular binding to particles and immune complexes that have activated complement. Decreases in expression of this protein and/or mutations in this gene have been associated with gallbladder carcinomas, mesangiocapillary glomerulonephritis, systemic lupus erythematosus, sarcoidosis and Alzheimer's disease. Mutations in this gene have also been associated with a reduction in Plasmodium falciparum rosetting, conferring protection against severe malaria. [provided by RefSeq, May 2020]

ENSG00000236911 (HGNC:40160):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016447097).
• BS2: High Homozygotes in GnomAd4 at 13 BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CR1	NM_000651.6	c.3994C>T	p.His1332Tyr	missense_variant	Exon 25 of 47	ENST00000367049.9	NP_000642.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CR1	ENST00000367049.9	c.3994C>T	p.His1332Tyr	missense_variant	Exon 25 of 47	5	NM_000651.6	ENSP00000356016.4

Frequencies

GnomAD3 genomes AF: 0.000858 AC: 129 AN: 150338 Hom.: 13 Cov.: 30

Gnomad AFR AF: 0.00267

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000481

GnomAD3 exomes AF: 0.000270 AC: 67 AN: 248580 Hom.: 8 AF XY: 0.000126 AC XY: 17 AN XY: 134890

Gnomad AFR exome AF: 0.00330

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000945 AC: 138 AN: 1460490 Hom.: 16 Cov.: 32 AF XY: 0.0000853 AC XY: 62 AN XY: 726586

Gnomad4 AFR exome AF: 0.00267

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000332

GnomAD4 genome AF: 0.000858 AC: 129 AN: 150338 Hom.: 13 Cov.: 30 AF XY: 0.000940 AC XY: 69 AN XY: 73438

Gnomad4 AFR AF: 0.00267

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000481

Alfa AF: 0.000235 Hom.: 3

ESP6500AA AF: 0.00389 AC: 14

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000265 AC: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2644C>T (p.H882Y) alteration is located in exon 17 (coding exon 17) of the CR1 gene. This alteration results from a C to T substitution at nucleotide position 2644, causing the histidine (H) at amino acid position 882 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Uncertain	0.99
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.68	.;.;.;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.016	T;T;T;T
MetaSVM	Benign	-0.87	T
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.12	T;T;T;T
Sift4G	Uncertain	0.013	D;D;D;T
Polyphen		0.98	.;.;.;D
Vest4		0.25
MVP		0.77
MPC		0.31
ClinPred		0.013	T
GERP RS		1.8
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201131753; hg19: chr1-207741210;